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01.03.11: Hematopoieses


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Slideshow is from the University of Michigan Medical School’s M2 Hematology / Oncology sequence

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01.03.11: Hematopoieses

  1. 1. Author: Ivan Maillard, M.D., Ph.D., 2009License: Unless otherwise noted, this material is made available under the termsof the Creative Commons Attribution–Non-commercial–Share Alike 3.0License: have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use,share, and adapt it. The citation key on the following slide provides information about how you may share and adapt thismaterial.Copyright holders of content included in this material should contact with any questions,corrections, or clarification regarding the use of content.For more information about how to cite these materials visit medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or areplacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to yourphysician if you have questions about your medical condition.Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers.
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  3. 3. HEMATOPOIESIS Ivan Maillard, MD-PhD Assistant Professor Center for Stem Cell Biology, Life Sciences InstituteDivision of Hematology-Oncology, Department of Medicine Department of Cell and Developmental Biology UM Medical School Winter, 2011
  4. 4. HEMATOPOIESIS  Topics of the course:   Location of hematopoiesis during embryogenesis and in the adult   Origins and properties of the hematopoietic stem cell   Assessment of hematopoietic precursors   Relationship of the stem cell to all classes of blood cells   Development of lymphocytes   Development of the erythroid, granulocytic, and megakaryocyte lineages   Differences in hemoglobin during development
  5. 5. What is Hematopoiesis?  Development of the cells of the blood system and of their supporting structures   Elements of the hematopoietic system •  Blood cellular elements: erythrocytes, megakaryocytes- platelets, white blood cells •  Proteins •  Stroma that supports blood development   Characterized by a regulated balance of progenitor self- renewal and commitment to differentiate   Organized as a hierarchy
  6. 6. Hematopoietic Hierarchy Differentiated cells Multipotency Self-renewal capacity Stem cell Signal(s)I. Maillard
  7. 7. Why understand the details?  Narrow homeostasis of blood cell numbers   If not actively maintained, hematopoietic failure   For example: 2 x 106 new red cells produced every second!  Hematopoietic response essential in many clinical situations   Infection, wound healing   Hemorrhage   Chemotherapy, bone marrow transplantation   …  Dysregulation of the hematopoietic program in hematological maligancies   Leukemia, lymphoma, multiple myeloma
  8. 8. Origins of Hematopoiesis  Primitive Hematopoiesis   Transient, primitive program   Begins in early embryogenesis   First 8 weeks: cells arise in the embryonic yolk sac  Definitive Hematopoiesis   What we see in the adult   Begins during fetal life in association with vascular structures (fetal aorta, placenta)   Expands in the fetal liver and spleen   In the late fetus the bone marrow becomes the main site of hematopoiesis
  9. 9. Shifting Sites of Human Hematopoiesis FETUS ADULT Yolk Sac Liver Bone marrow-axial skeleton and HEMATOPOIEIS Spleen Bone marrow distal long bones 1 2 3 4 5 6 7 8 9 10 20 30 40 50 60 70 Source Undetermined MONTHS YEARS
  10. 10. Primitive and definitive hematopoiesis Avian chimeras Mouse, HumanDieterlen-Lièvre, 1975 Primitive Definitive Hematopoiesis Hematopoiesis Dieterlen-Lièvre, 1975
  11. 11. Primitive Hematopoiesis Yolk sac Ema and Rossant, 2003 Endothelium Blood progenitorHemangioblast? I. Maillard
  12. 12. Early observations Anatomical Record (1917)Florence Sabin (1871-1953)
  13. 13. Morphology of the chick blastoderm Sabin (1920)
  14. 14. Angioblastic cords in the chick blastoderm Lumenization and endothelial morphology Blood islands Sabin (1920)
  15. 15. Sites of HematopoiesisMikkola and Orkin, 2005
  16. 16. Emergence of definitive hematopoietic stem cells I. MaillardAGM: aorta, gonad, mesonephros
  17. 17. I. Maillard
  18. 18. Essential Properties of Definitive Hematopoietic Stem CellsHematopoietic Stem Cell: •  Extensive self-renewal •  Quiescence (in steady-state conditions) •  Multipotency Broad differentiation capacity - maintains all different classes of blood cells and lymphocytes   Numbers are low   Cannot be detected by the naked eye in the bone marrow   Prospective identification relies on cell surface markers   In humans, the stem cell has not been as clearly defined as in the mouse
  19. 19. Hematopoietic Stem Cell Phenotype Best defined somatic stem cell! Weissman and collaboratorsKiel and Morrison (CD150+, CD48-)
  20. 20. How can we study hematopoietic stem and progenitor cells?  Transplantation models   Donor cells into mice whose blood cells have been destroyed   Can determine the developmental potential of a given population of blood progenitors   One single hematopoietic stem cell can repopulate all the blood cell lineages!  Cell culture techniques   BFU –Burst forming units •  Proliferate •  Not able to establish all cell lineages   CFU-Colony forming units •  Later cell than the burst forming unit •  Can repopulate a cell lineage but more restricted that the BFU
  21. 21. What directs hematopoietic stem celldifferentiation to specific blood lineages? Cytokines Transcription Growth factors factorsMicroenvironment Enforcement of lineage fate decisions
  22. 22. Hematopoietic differentiation Classical ModelWeissman and coll.
  23. 23. Hematopoietic Stem Cell Differentiation An Evolving Model Source Undetermined
  24. 24. Erythropoiesis  Development of red blood cells  Maintains a constant mass of red blood cells  Major component is hemoglobin   Three elements are required for synthesis: •  Globin protein chains •  Protoporphyrin •  Incorporation of iron  Morphologic characterization of different stages of red blood cell development is tightly coupled to hemoglobin synthesis
  25. 25. ERYTHROPOIESIS IL-3 GM-CSF -HSC CMP BFU-E CFU-E Erythropoietin Proerythroblast Basophilic erythroblast Polychromatophilic erythroblast Orthochromatophilic erythroblast Reticulocyte Red blood cell I. Maillard
  26. 26. Hemoglobin Synthesis α 100 90Hemoglobin % 80 70 ζ,ε γ 60 50 β 40 α,γ 30 20 10 1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7 Months (Fetus) Months (Newborn) 1-2 months 2-10 months Birth Gower-1 ζ2ε2 Hemoglobin F α2β2 appears Gower-2 α2ε2 (α2γ2) Hemoglobin F diminishes Portland ζ2γ2 α2β2 begins to appear Source Undetermined
  27. 27. Megakaryopoiesis  Generation of platelets that are critical for hemostasis   Small anucleate cells  Development characterized by endomitosis   Nucleus divides but cytoplasm does not  Single polyploid nucleus and increased cytoplasmic volume   Cytoplasm becomes demarcated at the end stage of megakaryopoiesis   Platelets are shed from mature megakaryocyte and leave behind nucleus
  28. 28. MEGAKARYOPOIESIS IL-3 GM-CSF -HSC CMP BFU-MK CFU-MK TPO Megakaryoblast (Stage I Megakaryocyte) Thrombopoietin (TPO) II IL-11 Megakaryocyte III IV Platelets I. Maillard
  29. 29. Platelet release by megacaryocytes Junt et al., Science 2007
  30. 30. Monopoiesis and Granulopoiesis  Derived from a common progenitor cell (GMP)  Cells of the monocyte series differentiate into tissue macrophages  Granulopoiesis involves the generation of cells that have prominent granules: neutrophils, eosinophils and basophils  Can be enhanced therapeutically   G-CSF, GM-CSF…  Mast cells that have basophilic granules are derived from the HSC and develop in tissues
  31. 31. MONOCYTE AND NEUTROPHIL DEVELOPMENT IL-3 GM-CSF - HSC CMP CFU-GM CFU-M CFU-G Myeloblast Monoblast M-CSF Promyelocyte G-CSF Promonocyte Myelocyte Monocyte Metamyelocte BandI. Maillard Mature Neutrophil
  32. 32. Lymphopoiesis  Lymphocytes are derived from primitive bone marrow progenitors that activate a lymphoid program   e.g. immune receptor gene rearrangement (T and B cells)  Sites of lymphoid development   T cells: thymus   B, NK cells: bone marrow  Morphologically similar, but identification with antibodies directed against proteins on the cell surface and flow cytometry  Heterogeneous populations   Function   Life span   Surface structures   Circulation in peripheral organs (spleen, lymph nodes, others)
  33. 33. B CELL DEVELOPMENTRepertoire development Immunoglobulin expressionHSC CLP Pro-B Pre-B Immature B IL-7, Flt3L Plasma Cell Antigen Mature Differentiation and B antibody secretion I. Maillard
  34. 34. T CELL DEVELOPMENT Thymus Periphery γδ γδ γδ CD4 CD4 CD4 T helper DN DN αβ DP CD8 CD8 CD8 Notch IL-7, Flt3L T cytotoxicHSC Repertoire development Differentiation I. Maillard
  35. 35. HEMATOPOIESIS  Topics of the course:   Location of hematopoiesis during embryogenesis and in the adult   Origins and properties of the hematopoietic stem cell   Assessment of hematopoietic precursors   Relationship of the stem cell to all classes of blood cells   Development of lymphocytes   Development of the erythroid, granulocytic, and megakaryocyte lineages   Differences in hemoglobin during development
  36. 36. Additional Source Information for more information see: 6: Ivan MaillardSlide 9: Source UndeterminedSlide 10: Dieterlen-Lièvre, 1975Slide 11: Ivan Maillard; Ema and Rossant, 2003Slide 13: Sabin (1920)Slide 14: Sabin (1920)Slide 15: Mikkola and Orkin, 2005Slide 16: Ivan MaillardSlide 17: Yokomizo, Dzierzak, and speck 2009Slide 19: Weissman and collaborators, Kiel and MorrisonSlide 22: Weissman and collaborators, Kiel and MorrisonSlide 23: Source UndeterminedSlide 25: Ivan MaillardSlide 26: Source UndeterminedSlide 28: Ivan MaillardSlide 29: Junt et al., Science 2007Slide 31: Ivan MaillardSlide 33: Ivan MaillardSlide 34: Ivan Maillard